Small pox vaccine contains live vaccinia virus, a virus in the orthopoxvirus family and closely related to variola virus, the agent that causes smallpox. Neutralizing antibodies induced by vaccinia vaccine are cross-protective for other Orthopoxviruses. Although the efficacy of vaccinia has never been demonstrated in controlled trials, epidemiologic studies did show an increased level of protection against smallpox which persists for 5 years or less after primary vaccination and substantial but waning immunity that can persist for more than 10 years. Antibody levels after re-vaccination can remain high longer, conferring a greater period of immunity than occurs after primary vaccination alone.
For most people, the vaccinia vaccine is safe and effective. In a non-immune person who is not immuno-suppressed, the expected response to primary vaccination is the development of papule at the site of vaccination 2-5 days after percutaneous administration of vaccinia vaccine. The papule becomes vesicular, then pustular, and reaches its maximum size in 8-10 days. The pustule dries and forms a scab, which separates within 14-21 days after vaccination, leaving a scar.
Most people experience normal, typically mild reactions to the vaccine, like swelling and tenderness of regional lymph nodes, fever, erythematous or urticarial rashes and inadvertent inoculation. Most of these resolve without any treatment.
Some people may experience moderate or severe reactions, which may require medical attention. These complications are rare but occur at least 10 times more often among primary vaccinees than among re-vaccinees and are more frequent among infants and immune-compromised subjects than among older children and adults. In the past, between 14 and 52 subjects per 1 million people vaccinated for the first time experienced potentially life-threatening reactions.
The following complications of vaccinia vaccination require medical attention:
Eczema vaccinatum: Serious skin rashes caused by widespread infection of the skin. Occurs in patients with history of eczema or atopic dermatitis. Lesions begin to appear at distant sites as the virus spreads throughout the body. Usually illness is mild and self-limiting, but can be severe or fatal. The most serious cases among vaccine recipients occur among primary vaccinees and are independent of the activity of the underlying eczema.
Progressive vaccinia (or vaccinia necrosum): Ongoing infection of skin with progressive tissue necrosis. The lesion may progress for months, and secondary lesions can develop elsewhere in the body. The infection is more common in primary vaccinees, immune compromised subjects and in children and is frequently fatal. Occurrence of this complication was influenced by the strain of vaccine virus and was higher in Europe than in the US.
Generalized vaccinia: Is characterized by a diffuse erythematous maculopapular rash indiscriminately scattered over the body. The papules become vesicles and heal over within 15 days. It is thought that generalized vaccinia results from circulatory dissemination of the virus in normal individuals. The irregularity of the lesions and the healthy immune system of affected patients differentiate this disease from erythematous rash and accidental vaccinia.
Post-vaccinal encephalitis: Inflammation of the brain. This is a rare and serious complication and the relationship with the vaccinia virus is still unknown. The encephalitis that occurs in children younger than 2 years is characterized by and incubation period of 6-10 days and is associated with degenerative changes in ganglion cells, perivascular hemorrhage, and generalized hyperemia of the brain. Symptoms are the same as those associated with general encephalitis, including intracranial pressure, myelitis, convulsions and muscular paralysis. A second form of the disease occurs in older children and adults. This is characterized by an incubation period of 11-15 days and is associated with signs of an allergic response with perivascular demyelination. Occurrence of this complication was influenced by the strain of vaccine virus and was higher in Europe than in the US.
Two emerging potentially fatal adverse effects of smallpox vaccination are myopericarditis and ischemic cardiac event. Patients who experience cardiac illness following vaccination report shortness of breath, palpitations, and chest pain. Death from myocardial infarction is a distinct possibility.
Based on past experience, it is estimated that between 1 and 2 people out of every 1 million people vaccinated may die as a result of life-threatening reactions to the vaccine.
Moreover, subjects with weakened immune systems or certain skin conditions are more likely to have severe reactions and are therefore excluded from vaccination with vaccinia, unless they have been exposed to smallpox virus.
Intravenous immunoglobulin (IVIg) is a well known medical product, which consists of a non-specific immunoglobulin solution obtained by combining plasma from a plurality of individuals. Vaccinia Immunoglobulin (VIG) is a solution of immune globulins obtained from plasma collected from subjects who were vaccinated with smallpox vaccine. The solution therefore contains a relatively high titre of anti-vaccinia antibodies.
The preparation of VIG commonly used was an intramuscular (im) product (VIG-IM), and was produced by Baxter Healthcare Corporation in the 1990s. Because it contained a high proportion of aggregated proteins, it was administered solely by the intra-muscular route and could not be used intravenously (iv). Since plasma donors are not selected for high anti-vaccinia antibody levels, the efficacy of VIG treatment is limited and high volumes or multiple injections are needed to reach an effective level.
In general an initial dose of 0.6 ml/kg body weight (about 100 mg/kg=˜7 gr/adult treatment) was injected intramuscularly and subsequent administration determined by the course of illness. In severe vaccinia complication such as cases of eczema vaccinatum and progressive vaccinia as much as 1-10 ml/kg were used. These large doses were split into smaller units, and injected intramuscularly at multiple sites spread out over time.
Following the recent threat of bio-terrorist attack, a major effort has been made to produce VIG for intravenous administration (VIG-IV). Preparations of VIG-IV are available (C-VIG, Cangene, Acambis/Baxter; Dyn port). No similar product is currently being developed in the EU. Treatment with VIG-IV requires medical care and therefore has to be administered within a medical center framework.
VIG has been indicated for accidental implantation involving extensive lesions, eczema vaccinatum (EV), generalised vaccinia (GV), and progressive vaccinia (PV). VIG is not recommended for mild instances of accidental implantation, mild or limited generalised vaccinia, erythema multiforme, or encephalitis post-vaccination. VIG can also be useful in treating ocular vaccinia that results from inadvertent implantation. When ocular vaccinia with keratitis is present, consideration of VIG should include the possible increased risk for corneal scarring.
It was suggested that vaccinia immune globulin is also of value in post-exposure prophylaxis of smallpox when given within the first week following exposure, and concurrently with vaccination. Vaccination alone is recommended for those without contraindications to the vaccine, unless greater than one week has elapsed after exposure. At this time, administration of both products, if available, is recommended.
U.S. Pat. No. 4,174,388 (McAleer et al) discloses hepatitis B immune globulin prepared from individuals who exhibit an increase in hepatitis B surface antibody of at least 2,000 PHA units/ml following immunization with hepatitis B surface antigen.
U.S. Pat. No. 4,617,379 (Dobkin et al) discloses the preparation of cytomegalovirus (CMV) hyperimmune serum globulin. The serum globulin is prepared from normal fresh plasma from donors who have not been vaccinated with a CMV vaccine and who have been screened for higher than normal titres of antibody to CMV. Plasma containing high titre antibody to CMV is pooled and fractionated to give the product.
U.S. Pat. No. 6,692,739 (Patti, et al) discloses a method and composition for the passive immunization of patients infected with or susceptible to infection from Staphylococcus bacteria. The composition is prepared from a donor plasma pool obtained by combining individual blood or blood component samples which have higher than normal titres of naturally occurring antibodies to an antigen of the Staphylococcus bacteria. The blood or blood component samples are obtained from a normal, un-vaccinated population. In an alternative embodiment, selected proteins or peptides are administered to a host to induce the expression of desired antibodies, the enhanced high titre serum or plasma pool is recovered from the host, and this pool is administered to a patient in need, optionally after purification and concentration.
WO 03/049117 discloses an intravenously injectable immune globulin having a high titre of antibody to Orthopoxvirus. The immune globulin is prepared by vaccinating a plurality of donors with an Orthopoxvirus vaccine, isolating plasma from each of the donors after a period of time sufficient to allow production of antibodies against the Orthopoxvirus vaccine, and preparing an intravenously injectable immune globulin from the plasma. Also disclosed is a method for treating or preventing an Orthopoxvirus infection, and a method of treating or ameliorating symptoms associated with adverse reaction to Orthopoxvirus vaccination.